Impairments in knowledge of social norms in presymptomatic, prodromal, and symptomatic frontotemporal dementia

Abstract INTRODUCTION We aimed to assess the knowledge of social norms in patients with behavioral variant frontotemporal dementia (bvFTD) with the Dutch version of the Social Norms Questionnaire (SNQ‐NL). METHODS The SNQ‐NL was administered in 34 patients with bvFTD, 20 prodromal mutation carriers, 76 presymptomatic mutation carriers, and 56 controls. Group differences and correlations with other neuropsychological tests and gray matter volume were examined. RESULTS Patients with bvFTD had lower total SNQ‐NL scores and more over‐adherence errors than presymptomatic mutation carriers and controls (P < 0.001). SNQ‐NL performance correlated with tests for executive functioning and social cognition, and with gray matter volume in bilateral frontal and unilateral temporal regions. DISCUSSION The SNQ‐NL can identify impairments in knowledge of social norms in bvFTD, highlighting its significance in clinical diagnosis and upcoming clinical trials. The SNQ‐NL currently fails to differentiate presymptomatic mutation carriers from controls; to this end, larger sample sizes from larger cohorts and longitudinal follow‐up are warranted. Highlights The Dutch version of the Social Norms Questionnaire (SNQ‐NL) is able to detect impairment in social cognition in symptomatic bvFTD patients. A trend towards a lower performance in prodromal mutation carriers was found. Performance on the SNQ‐NL is related to other measures of social cognition, executive functioning, and language. Lower SNQ‐NL performance is related to gray matter volume loss in bilateral frontal and temporal regions. The SNQ‐NL provides insight into the underlying cause of deficits in social cognition in bvFTD.

• Lower SNQ-NL performance is related to gray matter volume loss in bilateral frontal and temporal regions.
• The SNQ-NL provides insight into the underlying cause of deficits in social cognition in bvFTD.

BACKGROUND
Frontotemporal dementia (FTD) is a young-onset neurodegenerative disorder that is characterized by disproportional atrophy of the frontal and temporal lobes, causing a progressive decline of behavioral, motor, and cognitive abilities. 1The most common clinical presentations constitute the behavioral (bvFTD) and language variants (primary progressive aphasia [PPA]).In ≈ 30%, autosomal dominant mutations in chromosome 9 open reading frame 72 [C9orf72], microtubuleassociated protein tau [MAPT], and progranulin [GRN] are the leading cause of disease. 2,3Cognitive decline in genetic forms is increasingly being studied in longitudinal, multicenter cohorts, 3,4 as we can identify changes in presymptomatic mutation carriers years before overt disease, when pathological damage can still be halted or potentially even reversed. 3At present, however, no reliable cognitive biomarkers are available for FTD.
6][7] Social cognition is based on implicit and explicit processes 8,9 and consists of automatic processing of social information, understanding others, and consciously interpreting the emotional relevance of social information.The most-studied aspects of social cognition in patients with FTD are emotion recognition (ER; the implicit, rapid, and automatic processing of social stimuli) and Theory of Mind (ToM; the more explicit and controlled processing of social stimuli). 103][14][15][16] Nevertheless, how these social norms are presented in the presymptomatic and prodromal stages of FTD is still unknown.Identification of impairments in social cognition in these stages could, however, aid in early clinical diagnosis and allow disease monitoring, [17][18] both important factors with respect to upcoming disease-modifying trials for genetic FTD.In addition, it could allow the development of psychosocial interventions to strengthen social functioning in patients with (frontotemporal) dementia.

Participants
In n = 3]) were not fulfilling clinical diagnostic criteria for bvFTD 23 and had a CDR plus NACC-FTLD global score of 0. 22 Last, we included 56 cognitively healthy controls, consisting of healthy first-degree (i.e., mutation-negative) family members of patients with genetic FTD.

Consent statement
Ethical approval was obtained from the local ethics committee (MEC-2009-409) for the FTD-RisC study and the local biobank study that included participants enrolled from the outpatient memory clinic (MEC-2016-069).All participants gave written informed consent.

SNQ-NL
The SNQ-NL was administered to all participants as part of the routine neuropsychological assessment.The SNQ-NL consists of standardized instruction and 22 yes-no questions. 11Examples of questions are "Would it be socially acceptable to ask a coworker's age? (yes)" or "Would it be socially acceptable to spit on the floor?(no)."A total score was calculated by adding the number of right answers (0 to 22).
Two types of errors were scored in addition to the total score: break and over-adherence errors.A break error refers to endorsement of a socially inappropriate behavior (e.g., eating pasta with your fingers) as appropriate; an over-adherence error refers to endorsement of a socially appropriate behavior (e.g., wearing the same shirt twice in 2 weeks) as inappropriate. 26The break error score was the sum of all break errors made (0 to 12, a higher score reflects worse performance), the over-adherence error score was the sum of all over-adherence errors (0 to 10, a higher score reflects worse performance).Exclusion criteria for the study were having one or more missing items on the SNQ-NL.According to Knopman and Kukull, 27 a yes/no ratio score of < 0.3 or > 5 (the amount of "yes" answers divided by the amount of "no" answers) could indicate bias unrelated to the content of the items.In our study, 16 participants had a yes/no ratio score of < 0.3.We decided to include these participants to explore in which CDR plus NACC-FTLD groups these ratio scores were most common to shed light on their clinical relevance and provide an understanding of the test's outcomes.

RESEARCH IN CONTEXT
1. Systematic review: The authors reviewed the literature using traditional (e.g., PubMed) sources.While knowledge of social norms has not been studied systematically in different clinical stages in (genetic) frontotemporal dementia (FTD), there have been several publications describing neuropsychological test results, including social cognitive tests, in (genetic) FTD.Relevant citations are cited.
2. Interpretation: Our findings demonstrate a deficit in knowledge of social norms in the behavioral variant of FTD (bvFTD), even in a subset of prodromal individuals.
These results are consistent with previous studies showing deficits in social cognition in patients with bvFTD.
3. Future directions: Results from this study provide new insights and guidance for future research, such as investigating longitudinal trajectories of the SNQ-NL in genetic FTD to examine its significance in diagnostic processes and upcoming clinical trials.

Neuropsychological correlates
We explored the cognitive associations of the SNQ-NL by analyzing associations with other neuropsychological tests from the standardized neuropsychological test battery.We chose the neuropsychological tests based on the correlations found by van den Berg et al. 11 As a measure of social cognition, the Emotion Recognition Task (ERT 28 ) was included.The Trail Making Test (TMT) Part A 29 was included as a measure of information processing speed.TMT Part B, and category and letter fluency tests, 30 were included as measures of executive functioning.Last, the 60-item Boston Naming Test (BNT60) was included to measure language (naming) abilities. 31

Structural brain imaging and voxel-based morphometry
Images were acquired on a 3T MRI scanner (Philips Achieva).Participants from the FTD-RisC study underwent MR imaging during the same visit as the neuropsychological assessment.Participants from the outpatient memory clinic underwent MR imaging in a period of ± 3 months before or after SNQ-NL administration.All scans underwent extensive visual quality checks and images with large artifacts and/or incidental brain abnormalities unrelated to bvFTD were excluded from further analysis (n = 13).In total, 104 volumetric T1 scans were processed using the VBM Toolbox in Statistical Parametric Mapping 12 (SPM12; www.fil.ion.ucl.ac.uk/spm, version 7771, running in Matlab R2021b [Mathworks]).Images were realigned to correct for motion artifacts and then skull extracted and segmented to obtain the GM, white matter (WM), and cerebrospinal fluid (CSF) volumes.GM seg-mentations were transformed into Montreal Neurological Institute (MNI) space, modulated, and smoothed using a Gaussian kernel filter of 6 mm.A GM mask was applied by using the Masking toolbox. 32A partial correlation analysis was conducted between the SNQ-NL scores and the GM volumes by means of multiple regressions.

Statistical analysis
Statistical analyses were performed using SPSS statistics version

Demographic and clinical data
Demographic, clinical, and neuropsychological data are presented in Table 1.Patients with bvFTD and prodromal mutation carriers were older than presymptomatic mutation carriers and controls

SNQ-NL performance between groups
Patients with bvFTD had lower SNQ-NL total scores (mean or break errors were found between the genetic groups.

Neuropsychological correlates
Correlation coefficients per CDR plus NACC-FTLD score for each SNQ-NL score with other neuropsychological tests are presented in Table 2.In the control group, a higher SNQ-NL total score and fewer break errors were associated with better performance on the ERT (r = −0.35-0.32,P = 0.01-0.03).In the prodromal group, a higher SNQ-NL total score and fewer over-adherence errors correlated with better performance on TMT-B (r = −0.84-0.70,P < 0.01).
In patients, a higher SNQ-NL total score and fewer over-adherence errors were associated with better performance on TMT-A (r = −0.64-0.60,P = 0.01-0.02)and TMT-B (r = −0.55-0.66,P = 0.03-0.01).Fewer over-adherence errors were associated with better performance on category fluency (r = −0.79,P < 0.01).Moreover, higher performance on the SNQ-NL shows moderate correlations with the ERT in prodromal mutation carriers and patients; however, this was not significant (P = 0.06 and P = 0.

Neuroanatomical correlates
T1 scans of patients with bvFTD, and prodromal and presymptomatic mutation carriers (total n = 104) were analyzed to identify neuroanatomical correlates of SNQ-NL performance (Figure 2).VBM analyses showed a significant association between bilateral frontal (i.e., ventromedial prefrontal cortex, orbitofrontal cortex, anterior insula) and temporal regions (i.e., inferior temporal gyrus) and the SNQ-NL total score (Figure 2, Table S2 in supporting information): the lower the SNQ-NL performance, the lower the GM volume of abovementioned frontotemporal regions.

DISCUSSION
This study demonstrated the presence of impairment in knowledge of social norms in patients with bvFTD, and a negative trend in performance in a subgroup of prodromal mutation carriers.The difference in SNQ-NL total performance was mostly driven by the number of over-adherence errors.Performance on the SNQ-NL was significantly, though moderately, correlated with performance on the ERT in controls and TMT-A, TMT-B, and category fluency in affected participants.
In addition, lower SNQ-NL performance was related to lower GM volumes of bilateral frontal (ventromedial prefrontal cortex, orbitofrontal cortex, anterior insula) and temporal (inferior temporal gyrus) regions.
Taken together, these findings indicate that the SNQ-NL is a sensitive test for discriminating patients with bvFTD from presymptomatic mutation carriers and healthy controls.Lower performance on the SNQ-NL might indicate conversion in prodromal bvFTD.
4][35] In addition, we found moderate correlations between the SNQ-NL total and over-adherence error scores and measures for social cognition (controls) and executive functioning (prodromal mutation carriers and patients).It can be hypothesized that the SNQ-NL is associated with , 11 finding moderate correlations between the SNQ-NL and the ERT and verbal fluency.An explanation of the lack of significant correlations with over-adherence errors in the previous study could be the inclusion of patients with disorders other than bvFTD (i.e., AD and psychiatric disorders), while the current study solely focused on different clinical stages of FTD.In patients with bvFTD, we expect stronger associations with tests for mental flexibility, as this domain is-next to social cognition-often more impaired in bvFTD compared to AD and psychiatric disorders, and more strongly related to over-adherence errors.[38] Regarding brain imaging analyses, we found associations with the SNQ-NL total score and frontotemporal GM regions, specifically the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) as they are known to be involved in complex social behavior and emotioncognition interactions, 39 and are often the first regions to become affected in bvFTD. 40Moreover, the temporal lobes are involved in social semantic knowledge and higher social function through connections with the mPFC, OFC, and amygdala. 14,41No associations were found with subcortical structures, which is surprising as previous studies reported associations between social cognitive measures (i.e., ToM and social communication) and GM volume of primarily the thalamus, 42,43 but also the hippocampus and amygdala. 43Larger sample sizes are needed to further explore the neuroimaging correlates of SNQ-NL performance, given subcortical atrophy (most specifically of the thalamus) is a consistent finding in genetic subtypes of FTD 44,45 and is found to be associated with facial ER in GRN mutation carriers. 35 addition, patients with bvFTD made more over-adherence errors compared to prodromal and presymptomatic mutation carriers and controls.As a result, patients with bvFTD had more ratio scores of < 0. global decrease in cognitive functioning. 8,46However, in this study, over-adherence errors were associated with worse executive functioning.It is conceivable that patients with bvFTD have knowledge of social norms, but do not have the cognitive flexibility and/or language capabilities to evaluate/apply the social norm in different social contexts.For example, eating with your hands is often not acceptable (e.g., when eating pasta), but in some situations (e.g., when eating fries) it is.
These results correspond with findings from a previous study in which patients with bvFTD demonstrated impairments in the evaluation of social contexts. 47Social norm violations, as reflected in break errors, could be associated with disinhibition, leading to increased social rulebreaking in bvFTD. 11Although patients with bvFTD usually present more behavioral disinhibition, we did not find more break errors in our patient sample.A possible explanation could be the lack of sensitivity in the detection of impaired social behavior and rule-breaking by traditional neuropsychological measures and questionnaires, as proposed by Panchal et al. 14 Interestingly, MAPT mutation carriers performed slightly worse on the SNQ-NL and made more over-adherence errors compared to the other genetic groups; however, after correcting for global cognitive impairment this finding was not significant.Nevertheless, temporal involvement in MAPT mutation carriers may play a role in lower performance, as the temporal lobes are often affected in MAPT-related FTD, resulting in loss of memory, language, and semantic capabilities. 2,48,49The SNQ-NL might require these capabilities to adequately identify the social norms and to accurately respond to them.In addition, MAPT mutation carriers are known for their rapid cognitive decline once they become symptomatic, 2 probably causing lower performance on neuropsychological tests compared to patients with a GRN or C9orf72 mutation in their early symptomatic stages.
A strength of this study is the use of a cohort of well-defined patients with bvFTD and the use of a matched control group of mutationnegative family members.5] Nonetheless, the data of the current study should be interpreted in light of some limitations.One limitation is the rela- FTLD scores per genetic group), which has increased statistical power but could have obscured gene-specific effects.Another limitation lies in the construction of the SNQ-NL itself; it might not be sensitive enough to identify impairment in all stages of bvFTD (i.e., presymptomatic and prodromal) as it measures a modality of social cognition that also requires executive functioning, memory, and language with yes-no answers, not allowing for more nuanced responses.This limitation could have caused the absence of potential (subtle) differences in performance between genetic groups.Future studies should look for more implicit, innovative tests to measure social norms identification and knowledge, for example by using social situations in virtual reality.Furthermore, the CDR plus NACC-FTLD scoring comes with some limitations.The assessment of motoric and neuropsychiatric symptoms is currently not included in this staging method, causing a potential possibility that some patients with such symptoms are miscategorized as a score of 0.5 or ≥ 1 while these individuals are in fact in a more advanced disease stage (this applies especially to C9orf72 repeat expansion carriers).This could explain the higher variability in SNQ-NL scores that was observed in patients and in the prodromal group.Last, in the presymptomatic group, there is more variability in age.Young mutation carriers are also included, while we predict that the development of initial symptoms will be later (> 10 years) compared to the older mutation carriers.Future studies with larger sample sizes could divide the presymptomatic group into early-presymptomatic and latepresymptomatic groups to explore this further. 35In the current study, we decided against that (and added age as a covariate instead) due to the resulting small sample size in each group and the need for sufficient statistical power.
To summarize, we demonstrated significant impairment in the identification of social norms in patients with bvFTD and a trend toward a lower performance in prodromal mutation carriers, highlighting the SNQ's significance in the diagnostic work-up of memory clinics and upcoming clinical trials for FTD.The SNQ-NL currently fails to differentiate presymptomatic mutation carriers from controls and to this end, larger sample sizes from larger (international) cohorts and longitudinal follow-up that allows comparisons between early-presymptomatic and late-presymptomatic cases, and investigation of differential diagnostic performance to other neuropsychological tests, are still warranted.

ORCID
Liset de Boer https://orcid.org/0009-0007-7161-3559 total, we included 188 participants (age range 26-88).Participants were grouped by means of the Clinical Dementia Rating (CDR) plus Behavior and Language domains from the National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration (CDR plus NACC-FTLD 22 ) module.Patients with bvFTD (n = 34, mutation carriers n = 18, sporadic n = 16) received a CDR plus NACC-FTLD global score of ≥ 1, for whom a clinical diagnosis was obtained in a multidisciplinary consensus involving experienced neurologists, neuropsychologists, radiologists, and geriatricians according to the diagnostic consensus criteria for probable or definite bvFTD. 23Patients with other clinical syndromes within the FTD spectrum (e.g., PPA, corticobasal syndrome, progressive supranuclear palsy) and mixed types were excluded from our study to ascertain homogeneity of the sample and to minimize the influence of speech and/or language disorders on SNQ-NL performance.Prodromal mutation carriers (n = 20, mutation carriers n = 14, sporadic n = 6) had a CDR plus NACC-FTLD global score of 0.5.Presymptomatic mutation carriers (n = 76; C9orf72; n = 53, GRN; n = 35, MAPT; n = 19 or TAR-DNA-binding protein [TARDBP; 28.0.1.0(IBM Corp.) and GraphPad Prism 5.The significance level was set at P < 0.05 (two-tailed) across all comparisons and we implemented corrections for multiple testing.To compare demographic data between groups, we used general linear models with Tukey post hoc tests.We analyzed differences in sex using chi-square tests.The distribution of all SNQ-NL scores and the TMT-A and -B and BNT60 deviated from a normal distribution, hence non-parametric counterparts of the abovementioned tests were used.Quade non-parametric analyses of covariance (ANCOVAs) were conducted to compare the mean differences in SNQ-NL performance (total, break, and over-adherence error scores) across participant groups (n = 188), while controlling for the effects of age, sex, and years of education.A chi-square test was performed to analyze group differences in the number of ratio scores of < 0.3.To explore genetic effects, we pooled all mutation carriers (n = 110), irrespective of their clinical status due to small sample sizes, and divided them by genetic group (C9orf72, GRN, and MAPT).A Quade non-parametric ANCOVA was conducted to compare the mean differences in SNQ-NL performance (total, break, and over-adherence error scores) across the genetic groups while controlling for the effects of age, sex, years of education, and CDR plus NACC-FTLD global score.TARDP mutation carriers were excluded from this analysis due to the small sample size of this group.A partial correlation analysis per CDR plus NACC-FTLD global score was performed with age, sex, and years of education as covariates to analyze the relationships with SNQ-NL performance and the other neuropsychological measures.We used bootstrapping (n = 1000) to account for assumption relaxation and to estimate confidence intervals.The relationship of performance on each SNQ-NL score with GM volume was explored by using multiple regression models in the VBM analysis.Age, sex, years of education, and Total Intracranial Volume (TIV) were included as covariates.All comparisons were corrected for a family-wise error rate of 0.05.

F I G U R E 1
Mean and standard deviation of SNQ-NL performance per CDR plus NACC-FTLD group.*P < 0.05.CDR, Clinical Dementia Rating scale; NACC-FTLD, National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration module; SNQ-NL, Dutch version of the Social Norms Questionnaire these measures as it relies both on social cognition (knowledge of social norms) and executive functioning (evaluating social norms in different contexts).These findings are partially in line with the study of van den Berg et al.

F I G U R E 2
tively small sample sizes once stratified.Future studies should aim for larger study groups (e.g., by including [genetic] bvFTD patients from other countries) as well as investigate longitudinal data to create better profiles of social cognition.Because of these small sample sizes, we decided to pool our genetic groups (including all CDR plus NACC-Neuroanatomical correlates of performance on the Dutch version of the Social Norms Questionnaire total score.Results are shown on a study-specific T1-weighted magnetic resonance imaging template in Montreal Neurological Institute space.Results are corrected for family-wise error (P < 0.05).
Demographic and clinical data in the total sample (n = 188).
3.In previous work, SNQ over-adherence errors were described as non-specific and to be associated with anxiety, inattention, or a Correlation coefficients per clinical group (based on CDR plus NACC-FTLD score) between SNQ-NL scores and other neuropsychological tests.